Fosinopril formulation

ABSTRACT

A pharmaceutical formulation is provided comprising fosinopril which is the prodrug of an angiotensin converting enzyme (ACE) inhibitor, fosinoprilat. The formulation is characterized by comprising in the range of about 0.25 to about 5% glyceryl dibehenate which has been found to be a highly useful lubricant in the manufacture of tablets according to the present invention, enhancing the stability of fosinopril as compared to prior art formulations.

FIELD OF INVENTION

The present invention is within the field of pharmaceuticals,particularly relating to improved formulations of the ACE inhibitorprodrug fosinopril.

TECHNICAL BACKGROUND AND PRIOR ART

Fosinopril is the ester prodrug of an angiotensin converting enzyme(ACE) inhibitor, fosinoprilat. The compound can be used as anantihypertensive agent. Its ability to inhibit ACE and thus lower bloodpressure is disclosed in U.S. Pat. No. 4,337,201. The compound (thesodium salt, which is the commonly used drug form) is designatedchemically as L-proline4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]sodium,trans-, see Formula (I).

The prodrug is converted in vivo into the active component by hydrolysisof the diester sidechain. Fosinopril sodium has a relatively low bulkdensity, exhibits poor flow characteristics, and adheres to metalsurfaces during tableting. Fosinopril has been tableted by a wetgranulation process using magnesium stearate as a lubricant material.Tablets produced from such blend have low stability, are moisturesensitive and require the use of a protective package for a useful shelflife.

U.S. Pat. No. 5,006,344 suggests the use of sodium stearyl fumarate orhydrogenated vegetable oil instead of magnesium stearate, to increasethe stability of fosinopril tablets. The reference however, does notdiscuss why the two preferred lubricants are found to be better thanmagnesium stearate, or suggest other possible lubricants. It has beensuggested that the degradation of fosinopril in Mg stearate compositionsis due to the effect of the Mg metal ion (Thakur, A. B. et al. Pharm.Res. 10 (6) 800–809 (1993)).

It has now been found that fosinopril sodium tablets comprising glyceryldibehenate as lubricant have excellent stability. Glyceryl dibehenatehas several advantages when used in fosinopril compositions as comparedto other lubricants used in prior art compositions. In contrast to saltsof fatty acids and fatty acid derivatives including magnesium stearateor sodium stearyl fumarate, glyceryl dibehenate is a neutral andnon-metal containing compound.

In contrast to hydrogenated vegatable oil, glyceryl dibehenate ischemically a clearly defined substance and can be obtained with a welldefined particle size.

SUMMARY OF INVENTION

The present invention provides a pharmaceutical formulation comprisingin the range of about 1% to 25% fosinopril or a salt thereof, theformulation being characterized by comprising in the range of about 0.25to about 5% glyceryl dibehenate.

DETAILED DESCRIPTION

The present formulation is particularly useful in tablet formulations,however, it is as well contemplated that the formulations according tothe invention can be formulated for capsules, sachets, caplets or othersolid dosage forms. As mentioned the formulation comprises in the rangeof about 1% to 25% fosinopril or a related salt thereof, preferably thesodium salt, such as about 1–10%, including about 1–5%. The formulationis characterized by comprising in the range of about 0.25 to about 5%glyceryl dibehenate, such as in the range of about 0.5–5%, or about1–5%, e.g. in the range of about 1–2.5%, including about 1%, and about2%, or about 2.5% of glyceryl dibehenate. All percentages used hereinrefer to weight percentages if not otherwise noted.

Glyceryl dibehenate may be obtained by esterification of glycerol withbehenic acid (C 22:0 fatty acid). The product is provided commerciallyby Gattefossé s.a. under the tradename Compritol 888 ATO. Compritol hasa fatty acid composition with over 83% benehic acid, 40–60% of the fattyacids are in diester form (diglycerides), and 21–35% are in triesterform (triglycerides). Accordingly, useful embodiments of the inventioncomprise a lubricant formulation in the above amount comprising in therange of about 50–100 wt % of glyceryl di-and tribehenate, such as inthe range of about 55–95 wt %, including the range of about 70–80 wt %.Such lubricant formulations would generally contain glyceryl dibehenateand glyceryl tribehenate in a ratio ranging from about 1:1 to about 3:1.

The formulation of the present invention typically further comprisesconventional excipients such as a filler, a disintegrant, and a binder.In one embodiment the formulation comprises in the range of 30 to 85% ofa filler substance, which may be one of numerous substances generallyknown in the art, such as e.g. a saccharide (e.g. lactose or mannitol)or microcrystalline cellulose or a mixture thereof, and may furthercomprise in the range of 0.5 to 5 wt % of a disintegrant such ascrosslinked sodium carboxymethylcellulose (NaCMC), crosslinkedpolyvinylpyrrolidone or mixtures thereof. Suitable binders includepovidone (2-pyrrolidinone), hydroxypropyl cellulose, pregelatinizedstarch, gelatin and mixtures thereof. The formulations may additionallycomprise other commonly used excipients that are compatible with theactive ingredient such as pigments, colorants, sweeteners, taste-maskingagents and the like.

For production of tablets a direct compression or wet granulationprocess may be used, where the latter is presently preferred.

In certain embodiments the formulation of the invention furthercomprises in the range of about 0.5–50 wt % of a pharmaceutically activecompound selected from the group containing diuretics includinghydrochlorothiazide; antitussives including dextromethorphan,dextromethorphan hydrobromide, noscapine, carbetapentane citrate, andchlophedianol hydrochloride; antihistamines including chlorpheniraminemaleate, phenindamine tartrate, pyrilamine maleate, doxylaminesuccinate, and phenyltoloxamine citrate; decongestants includingphenylephedrine hydrochloride, phenylpropanolamine hydrochloride,pseudoephedrine hydrochloride, ephedrine; and alkaloids such as codeinephosphate, codeine sulfate, and morphine.

The following non-limiting examples illustrate in more detail apreferred embodiment of the invention and its advantages.

EXAMPLES Example 1

The following materials were combined by wet granulation to produce 5mg, 10 mg, and 20 mg fosinopril sodium tablets (tablet weight 100 mg,200 mg, 200 mg respectively):

Fosinopril sodium 5.0 mg 10.0 mg 20.0 mg Lactose monohydrate  59 mg  118mg  108 mg Starch, pregelatinized  12 mg   24 mg   24 mg (starch 1500)Crosslinked NaCMC   2 mg   4 mg   4 mg (croscarmellose sodium) Water,purified q.s. q.s. q.s. Microcrystalline cellulose  20 mg   40 mg   40mg Glyceryl dibehenate*   2 mg   4 mg   4 mg Compritol ™ 888 ATO,Gattefossé s.a., France

Example 2

Stability of tablets prepared in Example 1 and of marketed preparationwere tested at 40° C. for one month. Hydrolysis of fosinopril intofosinoprilat was assayed and measured as relative amount of initialamount of fosinopril.

Assay Fosinoprilat Tablets from Ex. 1 4.9 mg 1.7% Marketed prepn**. 4.9mg 2.6% **Dynacil ™ fosinopril sodium 5 mg tablets, containing sodiumstearyl fumarate as lubricant

The example demonstrates a surprisingly good stability of fosinoprilsodium tablets according to the present invention.

Example 3

The following materials are combined by wet granulation to producetablets with 10 mg fosinopril sodium and 12.5 mg hydrochlorothiazide(tablet weight 200 mg):

Fosinopril sodium  10.0 mg Hydrochlorthiazide  12.5 mg Lactosemonohydrate 105.5 mg Starch pregelatinized   24 mg Crosslinked NaCMC   4 mg Water purified q.s. Microcrystalline cellulose   40 mg Glyceryldibehenate    4 mg

1. A pharmaceutical formulation comprising in the range of about 1% to25% fosinopril or a salt thereof, the formulation characterized bycomprising glyceryl dibehenate as a lubricant agent.
 2. The formulationof claim 1 comprising the sodium salt of fosinopril.
 3. The formulationof claim 1 comprising in the range of about 0.25 to about 5% glyceryldibehenate.
 4. The formulation of claim 1 formulated in tablet dosageform.
 5. The tablet formulation of claim 4 produced by wet granulation.6. The formulation of claim 1 further comprising in the range of 30 to85 wt % of a filler substance, and in the range of 0.5 to 5 wt % of adisintegrant such as crosslinked sodium carboxymethylcellulose.
 7. Theformulation of claim 1 comprising about 5 wt % fosinopril sodium, about2 wt % of a lubricant formulation comprising in the range of about50–100 wt % glyceryl di- and tribehenate, in the range of about 50–70 wt% lactose monohydrate, about 20 wt % microcrystalline cellulose, andabout 2 wt % croslinked sodium carboxymethylcellulose.
 8. Theformulation of claim 1 further comprising 0.5–50 wt % of apharmaceutically active compound selected from the group containingdiuretics including hydrochlorothiazide; antitussives includingdextromethorphan, dextromethorphan hydrobromide, noscapine,carbetapentane citrate, and chlophedianol hydrochloride; antihistaminesincluding chlorpheniramine maleate, phenindamine tartrate, pyrilaminemaleate, doxylamine succinate, and phenyltoloxamine citrate;decongestants including phenylephedrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride,ephedrine; and alkaloids such as codeine phosphate, codeine sulfate, andmorphine.
 9. The formulation of claim 8 comprising 0.5–50 wt % ofhydrochlorothiazide.